Search

Necrotizing enterocolitis (NEC) is a devastating intra-abdominal emergency in the newborn period. The disease involves bowel wall inflammation, ischemic necrosis, eventual perforation, and the need for urgent surgical intervention. Unrecognized or left untreated, the neonate can decompensate quickly, often progressing to shock, multisystem organ failure, and eventual death. During the past several years, a number of basic science and clinical trials have been established in an attempt to understand the pathophysiology of NEC. As many researchers feel that NEC develops as an uncontrolled inflammatory response that leads to intestinal ischemia, a large number of studies have been focused on the inflammatory cascade and the role that cytokines play within that cascade. Although a large amount of data has been generated from these studies, the events leading to the ischemic injury of the intestine are still not fully understood. This article will therefore focus on the key cytokines involved with NEC, in an attempt to present the current literature and studies that support their involvement.

Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% +/- 3.36% versus 91.03% +/- 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% +/- 5.37%; milrinone, 77.65% +/- 4.42% versus vehicle: 74.42% +/- 7.54%). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.

Renal ischemia-reperfusion (I/R) is an important etiopathological mechanism of acute renal failure (ARF). Despite improvements in the treatment of ARF, it is associated with significant morbidity and mortality. I/R injury also occurs during renal transplantation and leads to reduced allograft survival. Sex differences have been found in I/R injury in many different organs including the kidney. Women have half the mortality of men in ARF. In animal models also, females are protected against renal I/R injury. The mechanisms by which sex affects the outcome to renal I/R injury are being actively investigated. This review will examine the evidence for gender differences in renal I/R injury and discuss the probable mechanisms by which sex affects the renal response to I/R injury.

Background Preconditioning is injury induced protection against subsequent insult. Studies have shown that both males and females may be preconditioned. Females appear to have an innate cardioprotection, therefore, we hypothesized that the preconditioning threshold may differ between males and females. Materials and methods Male and female rats were divided into five groups ( n = 4–9). Animals were given an intraperitoneal (i.p.) injection of 125, 250, or 500 micrograms/kilogram Salmonella typhimurium lipopolysaccharide (ETX) or 0.4-ml normal saline (NS). After 24-h incubation another i.p. injection of either 500 micrograms/kilogram ETX (injury dose) or NS was given and the animals incubated an additional 6 h. Shams received two injections of NS. Non-preconditioned rats (PC-) received NS followed by ETX. Preconditioned rats had i.p. injections of 125 μg/kg ETX (PC +125), 250 μg/kg ETX (PC +250), or 500 μg/kg ETX (PC +500) followed by the injury dose ETX. The rats were then anesthetized and myocardial function evaluated with the Langendorff perfusion model. Results PC +500 females were preconditioned and were able to maintain cardiac function similar to shams. Conversely, PC +125 females were not preconditioned with this stimulus and had a significant decrease in cardiac function similar to PC- rats. Male PC +500 and PC +125 rats, however, retained cardiac function comparable to shams, while PC- males showed a significant decrement. Conclusions Males and females may each be preconditioned by endotoxin; however, the preconditioning threshold is higher in females than males.

Hemorrhage, trauma, ischemia/reperfusion, burn, and sepsis each lead to cardiac dysfunction. These insults lead to an inflammatory cascade, which plays an important role in this process. Gender has been shown to influence the inflammatory response, as well as outcomes after acute injury. The mechanisms by which gender affects the inflammatory response to and the outcome of acute injury are being actively investigated. We searched PubMed for articles in the English language by using the search words sex, gender, estrogen, testosterone, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, and elucidate the various mechanisms by which gender affects the myocardial response to acute injury.

Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-alpha and IL-1beta via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-alpha and IL-1beta mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-alpha and IL-1beta mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.

Introduction. Acute renal failure (ARF) may be an ominous complication of circulatory arrest in cardiac surgical patients. Aprotinin is used as a therapeutic adjunct to preserving hemostasis by inhibiting protease-mediated fibrinolysis. Aprotinin has been shown to possess anti-inflammatory properties, which may be renal protective. However, it is unknown whether aprotinin decreases renal proinflammatory cytokine production following I/R. Indeed, other agents which have reduced renal IL-1beta and IL-6 have protected renal function in this setting. We hypothesized that aprotinin would decrease renal IL-1beta and IL-6 production following I/R. Methods. Adult male rats were subjected to unilateral I/R with varying lengths of both ischemia and reperfusion, with and without clinically relevant dosing and administration of aprotinin prior to the insult (clinically aprotinin is given prior to circulatory arrest). At various time points, the kidneys were harvested and the tissue homogenates were assayed for IL-1beta and IL-6 (ELISA). All experiments were approved by the Indiana University Animal Care and Use Committee (IACUC). Results. One-hour ischemia and 2 h of reperfusion significantly increased renal tissue IL-1beta and IL-6 levels (P < 0.05 versus sham, ANOVA with Bonferroni/Dunn). Aprotinin significantly (P < 0.05) decreased renal IL-1beta and IL-6 levels at this time point. Aprotinin also significantly decreased renal IL-1beta at the 1 h ischemia/4 h reperfusion time point. At no point did aprotinin increase production of either cytokine. Conclusions. Aprotinin decreases renal proinflammatory cytokine production following I/R. Further study will be needed to determine if aprotinin decreases renal tubular apoptosis and acute renal failure following such conditions. If so, aprotinin may be useful as an adjunct to preserving renal function following diverse planned ischemic events.

Background. Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. The concomitant production of proinflammatory mediators by the pulmonary artery itself may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC) mediated mechanism. Methods. Isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia (95% N2/5% CO2, pO2 = 30–35 mmHg) in the presence and absence of the protein kinase C inhibitor chelerythrine (1 μmol/L). Following 60 min of hypoxia, pulmonary artery rings were subjected to mRNA analysis for TNF-μ, IL-1β, and iNOS via RT-PCR. Data were analyzed using two-way analysis of variance (ANOVA) with post-hoc Bonferonni test or unpaired t tests with alpha level less than 0.05 considered statistically significant. Results. Hypoxia caused a biphasic contraction: an early and delayed contraction which occurred 1–3 and 15–20 min, respectively, after the onset of hypoxia. Hypoxic pulmonary artery tissue had increased expression of TNF-μ, IL-1β, and iNOS mRNA compared to normoxic controls. PKC inhibition significantly (P